Clinical characteristics.

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs), usually from the third decade onward. Many individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in 90% of affected individuals by age 30 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals, respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years. Life expectancy in NBCCS is not significantly different from average.

Diagnosis/testing.

The diagnosis of NBCCS is established in a proband who fulfills proposed diagnostic clinical criteria. Identification of a heterozygous germline pathogenic variant in PTCH1 or SUFU by molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Best provided by specialists experienced with the condition; avoidance of direct sun exposure through the use of complete sunblock and covering of exposed skin with long sleeves, high collars, and hats; early treatment of BCCs to ensure complete eradication of aggressive BCCs and to preserve normal tissue to prevent disfigurement; sonic hedgehog inhibitors such as vismodegib to treat severe BCCs; jaw keratocysts usually require surgical excision; treatment of medulloblastoma per neurosurgeon/oncologist.

Surveillance: Monitor head circumference throughout childhood; ophthalmology evaluations per ophthalmologist; feeding, hearing, and speech evaluation as needed in those with a history of cleft lip/palate; clinical exam for scoliosis as needed; skin examination at least annually; orthopantogram every 12-18 months beginning at age eight years to identify jaw keratocysts; developmental assessment and physical examination every six months until age five years due to increased risk for medulloblastoma; brain MRI in those with SUFU-related NBCCS every three to four months until age three years, every six months until age five years, annually until age eight years for medulloblastoma, and then every three to five years beginning at age 30 years for meningioma; ovarian ultrasound in women at age 18 years.

Agents/circumstances to avoid: Radiotherapy if there are alternative treatments, especially in childhood; diagnostic radiographs should be used sparingly; direct sun exposure should be limited, as excessive sun exposure increases the likelihood of developing BCCs.

Evaluation of relatives at risk: Because of the need for surveillance for complications of NBCCS (medulloblastoma in children; jaw keratocysts and BCCs in adults) and the need to avoid radiographs and sun exposure, clarification of the genetic status of at-risk relatives, including children, is appropriate.

Genetic counseling.

NBCCS is inherited in an autosomal dominant manner. Approximately 70%-80% of individuals with NBCCS have an affected parent and about 20%-30% have NBCCS as the result of a de novo pathogenic variant. Each child of an individual with NBCCS has a 50% chance of inheriting the disorder. If the NBCCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for NBCCS are possible.

Suggestive Findings

NBCCS should be suspected in individuals with the following findings, which constitute major or minor diagnostic criteria.

Major criteria

• Lamellar (sheet-like) calcification of the falx or clear evidence of calcification in an individual younger than age 20 years. Note: Falx calcification is nearly always present on AP skull radiographs after age 20 years in those with NBCCS.
• Jaw keratocyst. Odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency
• Palmar/plantar pits (≥2); particularly useful in diagnosis and more pronounced when the hands and feet are soaked in warm water for up to ten minutes. Pits may appear as white "punched-out" or pink "pin-prick" lesions.
• Multiple basal cell carcinomas (BCCs) (>5 in a lifetime) or a BCC before age 30 years. Provision needs to be made for decreased risk of BCC in individuals with dark skin and increased risk in those with light skin living in hot, sunny climates, particularly those with type 1 skin (that burns easily and does not tan) and red hair, and of this group, particularly those with the common MC1R variant (rs1805007), which can modify age of onset for NBCCS [Yasar et al 2015].
• First-degree relative with diagnosis of NBCCS

Minor criteria

• Childhood medulloblastoma (also called primitive neuroectodermal tumor)
  Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [Bree et al 2011]. The concern would be that this would reduce the specificity of diagnostic criteria, as individuals with medulloblastoma undergoing radiotherapy without NBCCS are likely to develop more than one BCC. Confining the medulloblastoma diagnosis to nodular/desmoplastic and disallowing BCCs occurring after radiotherapy as a major criterion may improve sensitivity without losing specificity. These changes have not yet been adopted. A consensus conference on screening recommendations convened by the American Association of Cancer Research did not propose adopting the Bree et al [2011] criteria [Foulkes et al 2017].
• Lymphomesenteric or pleural cysts
• Macrocephaly (OFC >97th centile)
• Cleft lip/palate
• Rib/vertebral anomalies observed on chest and/or spine radiograph: bifid/splayed/extra ribs, bifid vertebrae
  Note: (1) To verify a clinical diagnosis of NBCCS, AP and lateral radiographs of the skull, an orthopantogram, chest radiograph, and spine radiograph are usually necessary. (2) Radiographs should be avoided in children if they are not needed to confirm the diagnosis of NBCCS. (3) If radiographs have been taken previously (i.e., before the diagnosis of NBCCS is being considered), providers should obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (4) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings, as these can also be normal variations in the general population. (5) Radiographic findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly.
• Preaxial or postaxial polydactyly
• Ovarian/cardiac fibromas
• Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium)

Establishing the Diagnosis

The clinical diagnosis of NBCCS can be established in a proband based on proposed clinical diagnostic criteria [Evans et al 1993, Kimonis et al 1997], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in PTCH1 or SUFU identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous PTCH1 or SUFU variant of uncertain significance does not establish or rule out the diagnosis.

Clinical Description

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by macrocephaly, characteristic facial features, congenital rib/vertebral anomalies, ectopic calcification of the falx, basal cell carcinoma, and an increased risk of medulloblastoma and other tumors. To date, more than 500 individuals have been identified with PTCH1-related NBCCS and 176 individuals have been identified with SUFU-related NBCCS [Pál et al 2023, Lee et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

PTCH1. Individuals with PTCH1 missense pathogenic variants were diagnosed later (P=0.03) and were less likely to develop ten or more BCCs and jaw keratocysts (P=0.03) than those with other PTCH1 pathogenic variants.

Penetrance

Although NBCCS shows intra- and interfamilial variation in expression, experience clinically and from molecular testing is compatible with complete penetrance for PTCH1-related NBCCS, although with more subtle features in those with missense pathogenic variants [Author, personal observation]. The penetrance of SUFU pathogenic variants appears to be reduced.

Prevalence

The prevalence of NBCCS is reported to be between 1:18,976 and 1:30,827 [Evans et al 2010]. The true prevalence may be higher, as individuals with milder features may not be recognized.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with nevoid basal cell carcinoma syndrome (NBCCS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Manifestations should be treated by specialists (e.g., ophthalmologist, orthopedist, dermatologist, plastic surgeon, oral surgeon, neurosurgeon, oncologist, gynecologist) experienced with the condition (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Avoid unnecessary radiation exposure from the environment, investigative radiology, or radiotherapy treatment. Use of radiotherapy can lead to the development of thousands of basal cell carcinomas (BCCs) in the radiation field [Strong 1977, Evans et al 1991] and therefore should be avoided if there are alternative treatments, especially in childhood. If the treating team believes that no other treatment modality is possible, radiotherapy should be used through as few skin ports as possible.

Diagnostic radiographs should be used sparingly.

Avoid direct sun exposure as much as possible. Excessive sun exposure increases the likelihood of developing BCCs.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from surveillance for complications of NBCCS (most notably medulloblastoma in children and jaw cysts and BCCs in adults), early treatment, and avoidance of radiographs and sun exposure (see Agents/Circumstances to Avoid). Evaluations can include:

• Molecular genetic testing if the PTCH1 or SUFU pathogenic variant in the family is known;
• Clinical examination and radiographs of the skull for calcification if the pathogenic variant in the family is not known; these may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Since individuals with NBCCS have a large head circumference, a woman who is carrying an affected fetus should be assessed for the need for either early induction of labor or cesarean section delivery due to cephalopelvic disproportion.

Therapies Under Investigation

Aminolevulinic acid has been investigated for treatment of BCCs [Itkin & Gilchrest 2004, Oseroff et al 2005]. It is usually used in conjunction with photodynamic therapy [Loncaster et al 2009]. Topical treatment with 5-fluorouracil (Efudex^®) or imiquimod (5%) has been investigated [Kagy & Amonette 2000, Marks et al 2001, Stockfleth et al 2002]. Topical 5-fluorouracil appears effective for superficial multicentric BCCs without follicular involvement but should not be used for deeply invasive BCCs. A review suggested control rates approaching 90% for superficial BCCs and 50% for aggressive or nodular BCCs with imiquimod [Alessi et al 2009].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Nevoid basal cell carcinoma syndrome (NBCCS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent.
• A proband with NBCCS may have the disorder as the result of a de novo PTCH1 or SUFU pathogenic variant. The proportion of individuals with NBCCS with a de novo pathogenic variant is approximately 20%-30%.
• Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include a detailed skin examination, anterior to posterior (AP) and lateral radiographs of the skull, chest radiograph, and spine radiograph. Molecular genetic testing can be used to clarify the genetic status of a parent if a PTCH1 or SUFU pathogenic variant has been identified in the proband or other affected family member.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and germline mosaicism for PTCH1 or SUFU pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with NBCCS may appear to be negative as a result of failure to recognize the disorder in a family member, early death of the parent before the onset of symptoms, late onset of the disorder in the affected parent, or reduced penetrance in a parent heterozygous for a SUFU pathogenic variant. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If a molecular diagnosis has been established in the proband and the PTCH1 or SUFU pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016]. Although parental germline mosaicism has not been reported in NBCCS, low risks have been confirmed in the analogous situation in individuals with neurofibromatosis type 2 [Evans et al 2007].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for NBCCS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband

• Each child of an individual with NBCCS has a 50% chance of inheriting the disorder.
• The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the pathogenic variant [Reinders et al 2017].

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or known to have a PTCH1 or SUFU pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive genetic testing for at-risk asymptomatic family members requires prior identification of the PTCH1 or SUFU pathogenic variant in the family.
• Clinical examination and radiographs frequently act as a "genetic test" in an apparently unaffected individual. (Clinical examination and radiographs of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related nature of features in NBCCS.) Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of PTCH1 or SUFU.
• Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Parents often want to know the genetic status of their children prior to initiating screening to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.
  Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the NBCCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for NBCCS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PTCH1 encodes protein patched homolog 1 (PTC1), an integral membrane protein with 12 transmembrane regions, two extracellular loops, and a putative sterol-sensing domain. PTC1 binds the secreted factor sonic hedgehog (SHH) and functions as the SHH receptor. PTC1 represses the signaling activity of the coreceptor smoothened (SMO). When in complex with SHH, PTC1 is not a repressor, and signaling ensues. At least three forms of the PTC1 are present in human cells [Hahn et al 1996]. The suppression of the SHH signaling pathway through SMO has been the target of inhibitor drug therapies that partly mimic the loss of PTC1 function [Skoda et al 2018].

PTCH1 functions as a tumor suppressor in medulloblastoma as well as in basal cell carcinoma. Inactivation of the normal allele also appears to be the mechanism responsible for jaw keratocysts, whereas the congenital malformations are likely to result from alterations in the concentration of PTC1 in the extremely dosage-sensitive hedgehog signaling pathway [Villavicencio et al 2000].

SUFU encodes suppressor of fused homolog (SUFUH), which is a negative regulator in the hedgehog signaling pathway. Similarly to PTC1, loss of SUFUH function leads to upregulation of the pathway and increased risk of medulloblastoma and basal cell carcinoma.

Mechanism of disease causation. Loss of function

Author Notes

Dr Miriam Smith ([email protected]) is actively involved in clinical research regarding individuals with nevoid basal cell carcinoma syndrome (NBCCS). Dr Smith would be happy to communicate with persons who have any questions regarding diagnosis of NBCCS or other considerations.

Dr Smith is also interested in hearing from clinicians treating families affected by NBCCS in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Miriam Smith to inquire about review of PTCH1 or SUFU variants of uncertain significance.

Acknowledgments

The author acknowledges research support from the UK Gorlin Group.

Author History

D Gareth Evans, MD, FRCP (2002-2024)
Peter A Farndon, MD, FRCP; University of Birmingham (2002-2024)

Revision History

• 22 February 2024 (sw) Comprehensive update posted live
• 29 March 2018 (sw) Comprehensive update posted live
• 1 October 2015 (me) Comprehensive update posted live
• 7 March 2013 (me) Comprehensive update posted live
• 22 July 2010 (me) Comprehensive update posted live
• 25 January 2008 (me) Comprehensive update posted live
• 6 October 2004 (me) Comprehensive update posted live
• 20 June 2002 (me) Review posted live
• 21 November 2001 (pf) Original submission

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 2-12-24.

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